We will introduce examples of on-target cardiotoxicity of the widely used drugs, trastuzumab and imatinib, and probable off-target toxicity of another popular agent, sunitinib, to illustrate molecular mechanisms of cardiotoxicity. Trastuzumab The classical example of on-target cardiotoxicity of tyrosine kinase inhibition may be the cardiac effects of trastuzumab. improve anti-tumor activity with fewer toxic side-effects than traditional anti-cancer therapies; given the initial success of this approach, the number of targeted therapy drugs entering into development in the last five years has dramatically increased.6, 7 However, several recent studies have revealed unanticipated side-effects of targeted therapy, including cardiomyopathy and heart failure, the primary manifestations of cardiotoxicity we will be examining here.5, 8, 9 Herein, we will examine the potential risk of cardiomyopathy of targeted therapy, and the molecular mechanisms that underlie that risk. We will review the importance of tyrosine kinase signaling pathways both for oncogenesis and for the survival of normal cardiomyocytes. To understand basic mechanisms of cardiomyopathy of TKIs, it is critical to understand two general classes of toxicity. The first is on-target toxicity wherein the tyrosine kinase target regulating cancer cell survival and/or proliferation (and therefore is a good target in cancer therapy), also serves an important role in normal cardiomyocyte survival, and thus inhibition leads to myocardial dysfunction. Off-target toxicity occurs when a TKI leads to toxicity via inhibition of a kinase not intended to be a target of the drug. This type of toxicity is intrinsically related to two issues – 1) the inherent non-selectivity of TKIs and 2) a trend towards multi-targeting or purposefully designing drugs to inhibit a broad range of targets that include kinases regulating both tumorigenesis and tumor angiogenesis. Although multi-targeting may broaden efficacy of an anti-cancer agent, likelihood of toxicity would also increase. With the growing number of FDA-approved agents, and scores more in development,6, 7 some of these will inhibit novel kinase targets for which little or no CD44 clinical data exist on risk of heart failure or cardiomyopathy. Therefore, we will also review basic science studies that raise concerns over potential risk of cardiomyopathy in patients treated with drugs that inhibit these kinases. Finally, we will discuss cardiovascular considerations for development of future targeted therapy that may maximize anti-tumor effects, while minimizing cardiac effects in patients being treated with these potentially life-saving medications. Tyrosine Kinases in Signal Transduction Response to extracellular and intracellular stimuli is vital for all complex living organisms. Activation of signal transduction cascades allows a relatively small stimulus to be amplified into a larger biologic response, such as the re-programming of gene expression.10 Tyrosine kinases, of which there are approximately 90 in the human genome,11 play central roles in transducing extracellular signals (i.e. growth factors and cytokines) into activation of signaling pathways that regulate cell growth, differentiation, metabolism, migration, and programmed cell death (apoptosis). Tyrosine kinases are families of enzymes that catalyze transfer of a phosphate Penciclovir residue from ATP to tyrosine residues in other proteins (substrates). Phosphorylation can change activity, subcellular location, stability, etc. of the phosphylorated substrate protein. There are two major classes of tyrosine kinases. Receptor tyrosine kinases (RTKs) are embedded in the cell membrane with an extracellular ligand-binding domain and an intracellular kinase domain that signals to the interior of the cell. In contrast, non-receptor tyrosine kinases (NRTKs) are located within the cell. By their location, tyrosine kinases can mediate transduction of both extracellular and intracellular signals. Because of their critical role in normal cellular communication and maintenance of homeostasis, tyrosine kinase activity is tightly regulated. 10 Tyrosine kinases are normally quiescent until activated by extracellular stimuli or ligands, such as growth factors (e.g. vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF)) or intracellular stimuli (such as oxidant stress, activating non-receptor tyrosine kinases). An exquisite balance between activity of tyrosine kinases and of tyrosine phosphatases which mediate dephosphorylation of tyrosine residues and therefore take action in contra to kinases, settings the timing and duration of cell signaling. Irregular Tyrosine Kinase Activity and Penciclovir Malignancy: Malignant transformation and tumor angiogenesis Tyrosine kinase signaling is definitely central Penciclovir to both the malignant transformation of cells and tumor angiogenesis.12 Malignant transformation often results from dysregulation of tyrosine kinase signaling. Constitutive activation (i.e. on-going, actually in the absence of an activating transmission) of tyrosine kinases has been implicated in ~70% of cancers (Table 1).12, 13 In leukemias and stable cancers, the gene encoding the causal (or contributory) kinase is either amplified or mutated; the former prospects to overexpression of the kinase and the second option to a constitutively triggered state. Both mechanisms drive proliferation of the cancerous clonal cells and/or prevent them from undergoing apoptosis. Table 1 Kinase Inhibitors in Malignancy thead th align=”center” rowspan=”1″ colspan=”1″ Agent /th th align=”center” rowspan=”1″ colspan=”1″ Class /th th align=”remaining” rowspan=”1″ colspan=”1″ Target(s) /th th align=”remaining” rowspan=”1″ colspan=”1″ Malignancies /th th align=”remaining” rowspan=”1″ colspan=”1″ Cardiovascular toxicity / br / (Rate) / Type /th /thead imatinib br / (Gleevec)TKIABL1/2, PDGFR/, KITCML, Ph+ B-ALL, br / CMML, HES, GISTY / (low)*/ CHFdasatinib br / (Sprycel)TKIABL1/2, PDGFR/, KIT, SRC br / familyCMLY / (low to mod)* / CHF, br / generalized edemanilotinib br / (Tasigna)TKIABL1/2, PDGFR/, KITCMLY.